Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same

ABSTRACT

The present invention relates to co-extruded pharmaceutical compositions and dosage forms comprising an adverse agent, such as an opioid antagonist, which can be sequestered. The pharmaceutical compositions and dosage forms diversion of a dosage form containing an active pharmaceutical agent, such as an opioid. The present invention also relates to methods of treating a patient with such a dosage form, as well as kits containing such a dosage form with instructions for using the dosage form to treat a patient. The present invention further relates to a process for the preparation of such pharmaceutical compositions and dosage forms comprising co-extrusion of a core comprising an adverse agent and a sheath.

This application claims the benefit of U.S. Provisional Application No.60/464,295 filed Apr. 21, 2003, the entire disclosure being incorporatedherein by reference.

1. FIELD OF THE INVENTION

The present invention relates to co-extruded pharmaceutical compositionsand dosage forms comprising an adverse agent, such as an opioidantagonist, which can be sequestered. The pharmaceutical composition anddosage forms are useful for preventing or discouraging tampering, abuse,misuse or diversion of a dosage form containing an active pharmaceuticalagent, such as an opioid. The present invention also relates to methodsof treating a patient with such a dosage form, as well as kitscontaining such a dosage form with instructions for using the dosageform to treat a patient. The present invention further relates to aco-extrusion process for the preparation of such pharmaceuticalcompositions and dosage forms.

2. BACKGROUND OF THE INVENTION

Opioids, also known as opioid agonists, are a group of activepharmaceutical agents that exhibit opium- or morphine-like properties.More particularly, opioid agonists exhibit some form of opioid receptoractivity. Opioids are employed primarily as moderate to strong analgesicagents.

There have been previous attempts in the art to increase the tamperresistance of opioid analgesic dosage forms. Prior approaches todeveloping tamper resistant dosage forms have included combining anopioid agonist with an opioid antagonist. Particular examples of suchcombinations include compositions comprising naloxone and morphine oroxymorphone (U.S. Pat. No. 3,493,657 to Lewenstein et al.); methadoneand naloxone (U.S. Pat. No. 3,773,955 to Pachter et al.); methadol oracetyl methadol and naloxone (U.S. Pat. No. 3,966,940 to Pachter etal.); oxycodone and naloxone (U.S. Pat. No. 4,457,933 to Gordon et al.);and buprenorphine and naloxone (U.S. Pat. No. 4,582,835 to Lewis etal.).

U.S. Pat. No. 6,228,863 to Palermo et al. discloses an oral dosage formwhich combines an opioid agonist and an opioid antagonist such that atleast two separation steps are required to isolate the agonist.

U.S. Pat. No. 5,935,975 to Rose et al. discloses a method for treatingdrug dependency by the combined administration of the drug, i.e. theagonist, and an antagonist of the drug.

PCT Publication No. WO 01/58451 entitled “Tamper Resistant Oral OpioidAgonist Formulations,” is directed to decreasing the abuse potentialassociated with opioid analgesic dosage forms by the inclusion of asequestered opioid antagonist in an opioid agonist dosage form.

In addition, it is known in the pharmaceutical art to prepare oraldosage forms which provide for controlled release of therapeuticallyactive agents. Such controlled release compositions are used to delayabsorption of at least a portion of the dose of the agent until it hasreached certain portions of the gastrointestinal tract. Such controlledrelease of the agent serves to maintain a desired concentration of theagent in the blood stream for a longer duration than would occur ifconventional immediate or rapid release dosage forms were to beadministered.

Over the years, several different methods of preparing controlledrelease pharmaceutical dosage forms have been suggested, including, forexample, extrusion, granulation, coating beads and the like.

There remains a need in the art for improved tamper resistant dosageforms and improved techniques for their preparation.

3. SUMMARY OF THE INVENTION

The present invention relates to co-extruded, pharmaceuticalcompositions and dosage forms comprising an adverse agent, which can bea sequestered adverse agent, and co-extrusion methods for making suchcompositions and dosage forms. The present invention also relates tomethods of treating a patient with such pharmaceutical compositions ordosage forms, as well as kits comprising such pharmaceuticalcompositions or dosage forms and instructions directing the usage of thecomposition or dosage form to treat a patient.

In one embodiment, the invention relates to dosage forms comprising aplurality of co-extruded particles comprising an adverse agent, whichcan be a sequestered adverse agent. The adverse agent particles cancomprise a core and a sheath which at least partially surrounds thecore. The core can preferably comprise an adverse agent and at least onehydrophobic material and the sheath may preferably comprise at least onehydrophobic material. In one embodiment, the adverse agent is presentonly in the core. In another embodiment, the sheath is substantiallydevoid of an adverse agent. The dosage forms in accordance with thepresent invention include oral dosage forms, such as capsules ortablets, rectal suppositories and vaginal suppositories.

In another embodiment, the invention relates to dosage forms comprisinga plurality of first particles comprising an active agent, and aplurality of second particles comprising an adverse agent, which can bea sequestered adverse agent. The second particles comprise a corecomprising a sequestered adverse agent and a sheath.

In one embodiment, the invention also relates to dosage forms comprisinga plurality of first particles comprising an opioid agonist, wherein thefirst particles provide controlled release of the opioid agonist uponadministration to a patient; and a plurality of co-extruded secondparticles comprising a core comprising a sequestered adverse agent and asheath.

In certain embodiments, the present invention also relates to methods offorming a plurality of sequestered adverse agent particles comprisingforming a sheath comprising a hydrophobic material and a core comprisinga sequestered adverse agent and a hydrophobic material, wherein thesheath at least partially surrounds the core.

In yet another embodiment, the invention relates to methods of making adosage form comprising: (i) forming a plurality of first particlescomprising an active agent; (ii) forming a plurality of second particlescomprising an adverse agent by forming a core composition and a sheathcomposition to form a strand, wherein the sheath composition comprises ahydrophobic material and radially surrounds the core composition atleast partially and the core composition comprises the adverse agent anda hydrophobic material and cutting the strand to form a plurality ofsecond particles; and (iii) adding the first particles and the secondparticles together in a form suitable for administration to a patient.

The present invention further relates to methods of treating a patient,comprising administering a dosage form of the invention to the patient.In one embodiment of the invention, the patient is treated for pain.

The present invention also includes a method of reducing abuse, misuseor diversion of a dosage form for treating pain, comprisingadministering to a patent in need thereof a dosage form of theinvention.

In still another embodiment, the invention relates to kit for treatingpain in a patient, comprising at least one dosage form of the inventionand a set of instructions describing the use of the dosage form to treatthe patient. In one embodiment of the invention, the kit is for treatinga patient's pain.

The present invention may be understood more fully by reference to thefollowing detailed description and examples, which are intended toexemplify non-limiting embodiments of the invention.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of one embodiment of an adverseagent-containing particle of the present invention, which comprises acylindrical particle (10) containing a sequestered adverse agent whereina core (12) comprises an adverse agent and the core is radiallysurrounded by a sheath (14).

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Definitions

Any reference herein to any pharmaceutical agent, such as an activeagent, an adverse agent, an opioid agonist or an opioid antagonist,shall, unless otherwise stated, include any pharmaceutically acceptableform of such pharmaceutical agent, such as the free form, anypharmaceutically acceptable salt form, any pharmaceutically acceptablebase form, any pharmaceutically acceptable hydrate, any pharmaceuticallyacceptable solvate, any stereoisomer, any optical isomer, as well as anyprodrug of such pharmaceutical agent and any pharmaceutically activeanalog of such pharmaceutical agent, and mixtures of any of theforegoing.

The phrase “pharmaceutically acceptable salt,” as used herein, can be asalt formed from an acid and the basic group, such as a nitrogen group,of an active agent or an adverse agent. Generally, examples of suchsalts include, but are not limited, to sulfate, citrate, acetate,oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, glubionate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” can alternatively be a salt preparedfrom an active agent or an adverse agent having an acidic functionalgroup, such as a carboxylic acid or sulfonic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Generally,examples of such bases include, but are not limited to, hydroxides ofalkali metals such as sodium, potassium, and lithium; hydroxides ofalkaline earth metal such as calcium and magnesium; hydroxides of othermetals, such as aluminum and zinc; ammonia, and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; N-methylamine,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N, N,-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

A “patient” or “animal” is preferably a mammal, and includes, but is notlimited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit, and guinea pig, and most preferably ahuman.

As used herein, the phrase “active agent” refers to a pharmaceuticalagent that causes a biological effect when absorbed into the bloodstream of a patient.

As used herein, the phrase “adverse agent” refers to a pharmaceuticalagent that partially or completely negates or reverses at least onebiological effect of the active agent, e.g. euphoric effect, or producesone or more unpleasant physiological reactions, e.g., vomiting, nausea,diarrhea, bad taste, when absorbed in sufficient amount into the bloodstream of a patient or animal.

As used herein, the term “controlled release” refers to the in vivorelease of an active agent from a dosage form following administrationat a rate which will provide a longer duration of action than a singledose of the normal (i.e., immediate release) dosage form. For example, atypical immediate release oral dosage form may release the drug, e.g.,over a 1 hour interval, as compared to a controlled release oral dosageform which may release the drug, e.g., over a 4 to 24 hour interval.

As used herein, the phrase “opioid agonist” refers to an active agentwhich binds, optionally stereospecifically, to any one or more ofseveral subspecies of opioid receptors and produces agonist activity.

As used herein, the phrase “opioid antagonist” refers to an adverseagent that either reduces at least one biological effect of an opioidagonist, e.g., euphoric effect, or elicits at least one unpleasantphysiological reaction when absorbed in sufficient amount into the bloodstream of a patient or animal.

As used herein, the phrase “sheath substantially devoid of an adverseagent” refers to a sheath that does not contain any adverse agent exceptfor, possibly, small amounts which may have migrated into the sheathfrom an extruded or co-extruded component, e.g., the core.

5.2 Dosage Forms Comprising an Adverse Agent

In one embodiment, the adverse agent is not sequestered. In thatembodiment, the adverse agent can be released in vivo at any rate,including but not limited to immediate release or controlled release.

As stated above, one embodiment of the present invention is directed toco-extruded pharmaceutical compositions and dosage forms comprising anadverse agent, which can be a sequestered adverse agent, and to methodsof making such compositions and dosage forms.

In one embodiment, the invention relates to dosage forms comprising aplurality of co-extruded particles comprising a sequestered adverseagent. Those compositions and dosage forms of the invention areformulated or made in a manner which greatly reduces, limits or preventsthe in vivo release or absorption of the sequestered adverse agent intothe blood stream following administration as intended of the intactdosage form to a patient. Thus, only a small amount, preferably lessthan about 10% by weight and more preferably less than about 1% byweight or none, of the adverse agent present in the dosage form isreleased in vivo or absorbed into the blood stream following theadministration as intended of an intact dosage form to a patient. Whenthe adverse agent is an opioid antagonist, preferably less than about0.5 mg, and more preferably less than about 0.05 mg, of the opioidantagonist is released in vivo following administration as intended ofthe intact dosage form to a patient.

The adverse agent can be sequestered by co-extruding: a) the adverseagent with a material which limits or delays the in vivo release of theadverse agent to form a core; and b) a sheath which at least partiallycovers or surrounds the core. In one embodiment, the adverse agent canbe extruded with at least one hydrophobic material and, optionally,binders, plasticizers and/or excipients. In one embodiment, the sheathcan comprise at least one hydrophobic material and, optionally, binders,plasticizers and/or excipients. The core is at least partiallysurrounded or covered by the sheath, and a portion of the adverseagent-containing core can be exposed. In one embodiment, the sheathcovers or surrounds a majority of the core. For example, when the coreis cylindrical, the sheath can radially surround the length of the corewhile leaving the ends of the core exposed in the axial direction.

In one embodiment, the present invention relates to solid dosage formscomprising a plurality of co-extruded particles comprising a sequesteredadverse agent, wherein the particles comprise a core containing theadverse agent and the core is at least partially surrounded by a sheath.The particles are made by co-extrusion of the core and the sheath.Preferably, the sheath surrounds a majority, but not all, of the corecomponent. In one embodiment, the co-extruded, sequestered adverse agentparticle comprises an adverse agent-containing core and a sheath; thecore comprising an adverse agent and a hydrophobic matrix material; andthe sheath comprising a hydrophobic matrix material; wherein the core isat least partially surrounded by a sheath.

In one embodiment, the invention relates to dosage forms comprising: (i)a plurality of first particles comprising an active agent; and (ii) aplurality of co-extruded second particles comprising a core comprising asequestered adverse agent and a sheath, as well as methods of theirpreparation and use. In one embodiment, co-extruded particles containinga sequestered adverse agent (“sequestered adverse agent particles”) canbe combined with particles comprising an active agent to form a dosageform for administration to a patient. For example, a plurality ofco-extruded, sequestered adverse agent particles and a plurality ofparticles containing an active agent (“active agent particles”) can beplaced together in a capsule or compressed together to form a tablet,caplet, suppository or other dosage form.

The dosage forms of the invention can be administered orally, such as inthe form of a tablet or capsule, or rectally or vaginally in the form ofa suppository. In a preferred embodiment, the invention is directed tooral dosage forms.

In one embodiment, the sequestered adverse agent can be incorporatedinto small particles, such as, for example, particles having a size offrom about 0.1 mm to about 3.0 mm in all dimensions. The particles canhave any shape, such as cylindrical, spherical, square or irregular.

In certain embodiments, the adverse agent can be present throughout theco-extruded, sequestered adverse agent particle. In one embodiment, theadverse agent can be present in only the core, or in both the core andthe sheath. In another embodiment, the adverse agent can be present inone or more inner layers of a co-extruded, multilayer particle.

Multiparticulate extrudates of the invention can be compressed into anoral tablet using conventional tableting equipment and standardtechniques. Techniques and compositions for making tablets (compressedand molded), capsules (hard and soft gelatin) and other forms of pillsare also described in Remington's Pharmaceutical Sciences (Arthur Osol,editor), 1553-1593 (1980), incorporated by reference herein.

In one embodiment, an oral dosage form is prepared to include aneffective amount of melt-extruded multiparticulates (“MEMs”) within ahard or soft gelatin capsule. For example, a plurality of co-extrudedMEMs containing an adverse agent and a plurality of MEMs containing anactive agent can be placed in a gelatin capsule in an amount sufficientto provide an effective sustained-release dose of the active agent wheningested and contacted by body fluid, without significant release of thesequestered adverse agent. Alternatively, only the adverse agent can beformulated in MEMs.

In another embodiment, the MEMs can be compressed into tablets as setforth in U.S. Pat. No. 4,957,681 (Klimesch, et al.), which is expresslyincorporated herein by reference.

In certain embodiments, in the co-extruded, adverse agent containingparticles, the adverse agent is present only in a core (“adverse agentcore”) of a particle having a core and a sheath. The adverse agent coreis surrounded at least partially by a sheath. Both the core and thesheath preferably comprise at least one hydrophobic material which actsas a retarding agent to limit the in vivo dissolution of the particleafter administration. The hydrophobic material of the core may or maynot be the same as the hydrophobic material of the sheath. The particlesize of the adverse agent-containing particle is preferably from about0.1 mm to about 5.0 mm in all dimensions and, more preferably, fromabout 0.1 mm to about 3.0 mm in all dimensions. In one preferredembodiment, the adverse agent is sequestered within the core of acylindrical particle, and the core is radially surrounded by the sheath,leaving the core exposed at one or both ends of the co-extruded,cylindrical particle. Such particle can be manufactured by co-extrusionof the core and the sheath, followed by rendering the co-extruded strandinto particles, as discussed in further detail below.

In certain embodiments, the present invention includes a dosage formwhich includes a plurality of first particles containing an active agentand a plurality of co-extruded second particles containing a sequesteredadverse agent. In certain embodiments, the active agent particles areformulated to provide controlled release of the active agent in vivoover at least 8 hours, preferably over at least 12 hours, morepreferably over at least 24 hours, or longer. The active agent particlescan be made according to any method known in the art, such as byextrusion, melt-extrusion, granulation, coating inert beads, etc.

In certain embodiments, the active agent particles and the co-extruded,sequestered adverse agent particles are similar, and preferably,identical in size and appearance, to reduce the likelihood that theycould be manually separated from each other.

The co-extruded, sequestered adverse agent particles are formulated sothat only a relatively small amount, and preferably none, of thesequestered adverse agent is released in vivo when the co-extruded,sequestered adverse agent particles are administered intact to apatient, as intended.

When an intact dosage form including active agent particles andco-extruded, sequestered adverse agent particles is administered to apatient, only a relatively small amount, and preferably almost none, ofthe sequestered adverse agent is released in vivo, whereas the activeagent is released at the intended rate, which can vary from immediaterelease to controlled release. However, when a dosage form comprisingactive agent particles and co-extruded, sequestered adverse agentparticles is tampered with, e.g., chewed, crushed, ground or dissolved,particularly in a solvent with heat (e.g., greater than from about 45°C. to about 50° C., up to about 100° C. or above), then the amount ofadverse agent available for absorption into the body is substantiallyincreased. The adverse agent is then available to exert its effect byeither reducing at least one effect of the active agent, e.g., euphoriceffect, or eliciting one or more unpleasant effects in the patient.Thus, where the adverse agent is an antagonist of the active agent, atleast one effect of the active agent is preferably substantiallydiminished, or even eliminated, by the effect of the adverse agent. Forexample, where the active agent is an opioid agonist and the adverseagent is an opioid antagonist, a greatly increased amount of opioidantagonist will become bioavailable when the dosage form is tamperedwith, interfering with opioid-receptor binding and reducing the opioidagonist's euphoric effect. Accordingly, only patients who take thedosage form of the present invention as intended, i.e., as an intactdosage form, will experience substantially the full pharmacologicaleffect of the therapeutic agent. Where the adverse agent is an emeticagent and the dosage form is tampered with, the immediate release andabsorption of the emetic agent will induce nausea and/or vomiting todiscourage the user from tampering with the dosage form and also toremove the therapeutic agent from the subject's body. Abuse of theactive agent in the dosage form will thus become less desirable becauseof the undesirable effects caused by the adverse agent.

When administered intact to a patient, the in vivo release of anyadverse agent from the dosage form will preferably be sufficiently lowso that it will not substantially reduce the benefits of the activeagent or produce any unpleasant physiological reaction. The release rateof the adverse agent will be determined in large part by the compositionof the adverse agent core and the sheath of the co-extruded, sequesteredadverse agent particle. The co-extruded, sequestered adverse agentparticle will preferably release less than about 10% by weight and, morepreferably, less than about 1% by weight or none, of the adverse agentin vivo following administration of the intact dosage form. When theadverse agent is an opioid antagonist, the sequestered adverse agentparticles, in total, will preferably release less than about 0.5 mg,more preferably less than about 0.05 mg, of the opioid antagonist invivo following administration of the intact dosage form. For example,when the oral dosage form contains 5.0 mg of sequestered opioidantagonist and a dissolution test is conducted using the USP BasketMethod (USP Type I basket, 100 rpm; 700 ml simulated gastric filled, pH1.2 without enzyme; 37° C. for 1 hour followed by 900 ml simulatedintestinal fluid; pH 7.5 without enzyme for the duration of the test),the quantity of opioid antagonist released in a simulatedgastrointestinal fluid over 36 hours is less than 0.5 mg, and morepreferably less than 0.05 mg.

In one embodiment of the invention, the active agent particles and theco-extruded, sequestered adverse agent particles are approximately, andpreferably exactly, the same color, size and shape so as to make itdifficult to distinguish the two types of particles from each other.Both types of particles can be covered by a cosmetic coating so as torender them similar in appearance. Any known type of cosmetic coatingused for pharmaceutical oral dosage forms can be used so long as thedissolution pattern of the two particle types achieve the intendedpurpose of the invention.

In certain embodiments, either the dosage form or the active agentparticles and/or the co-extruded, sequestered adverse agent particlescan be cured by exposure to prolonged elevated temperatures in order toachieve increased stability. As used herein, the term “curing” means theheat treatment of the dosage form (or intermediate product) for purposesof obtaining a stabilized final dosage form. As will be understood bythose skilled in the art, when the formulations of the inventionincorporate a polymer as part or all of the hydrophobic retarding agent,a heat treatment causes a curing effect and the polymer possiblycross-links with itself into a more stable state. When the formulationsof the invention include a hydrophobic material such as, e.g.,hydrogenated vegetable oil or stearyl alcohol, the heat treatment may bemore akin to annealing of the formulation rather than a curing of thepolymer. However, for purposes of the present invention, the use of theterm “curing” is deemed to encompass both curing and annealing. Insituations where the hydrophobic material includes only a wax-likesubstance, curing can be accomplished at a temperature from about 35° C.to about 65° C., for a time period sufficient to achieve maximumstability, such as for a time period from about 4 to about 72 hours. Inother embodiments, curing is conducted at a temperature of from about40° C. to about 60° C., for a time period from about 5 to about 48 hoursor more, and preferably at least about 24 hours. Suitable curing timesthat achieve the intended result of a stabilized dosage form can bedetermined by those of skill in the art.

5.3 Adverse Agent

As noted above, the present invention is directed to co-extruded dosageforms and pharmaceutical compositions comprising a sequestered adverseagent, as well as methods for making and administering such dosage formsand compositions. In one embodiment, the invention relates to dosageforms comprising a plurality of co-extruded particles comprising asequestered adverse agent.

The sequestered adverse agent can be any pharmaceutical active agentwhich at least partially reduces or blocks the biological effect of anactive agent or which creates an unpleasant effect when absorbed into ananimal's or a patient's blood stream. Examples of adverse agentsinclude, but are not limited to, antagonists of any therapeuticallyactive agonist. When an opioid agonist is used as the active agent inthe dosage form of the present invention, an opioid antagonist can beused as the adverse agent. Likewise, when a benzodiazepine is used asthe active agent in the dosage form of the present invention, abenzodiazepine antagonist can be used as the adverse agent. When abarbiturate is used as an active agent in the dosage form of the presentinvention, a barbiturate antagonist can be used as the adverse agent.When an amphetamine is used as an active agent in the dosage form of thepresent invention, an amphetamine antagonist can be used as the adverseagent. When the active agent is toxic when dosed above its normaltherapeutic range, i.e., when there is a significant potential for anoverdose, then an antidote of the toxic active agent can be used as theadverse agent.

In one embodiment, the adverse agent is an opioid antagonist. Opioidantagonists useful in the present invention include, but are not limitedto, naloxone, naltrexone, nalmefene, nalbuphine, nalorphine,cyclazacine, cyclazocine, levallorphan, pharmaceutically acceptablesalts thereof, and mixtures thereof.

Useful opioid antagonist salts include salts formed from an acid and thebasic nitrogen group of an opioid antagonist. Examples of opioidantagonist salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

Other opioid antagonist salts include salts prepared from an antagonisthaving an acidic functional group, such as a carboxylic acid or sulfonicacid functional group, and a pharmaceutically acceptable inorganic ororganic base. Suitable bases include, but are not limited to thoseidentified above in Section 5.1 in the paragraph which references theterm “pharmaceutically acceptable salt”.

In certain embodiments, the opioid antagonist is nalmefene, naloxone,naltrexone, or a pharmaceutically acceptable salt thereof. In anotherembodiment, the opioid antagonist is a naltrexone salt, such asnaltrexone hydrochloride.

Benzodiazepine antagonists that can be used as the adverse agent of thepresent invention include, but are not limited to, flumazenil.

Barbiturate antagonists which can be used as the adverse agent of thepresent invention include, but are not limited to, amphetamines, asdescribed herein.

Stimulant antagonists that can be used as the adverse agent of thepresent invention include, but are not limited to, benzodiazepines,described herein.

In another embodiment of the present invention, the adverse agent is anagent that causes an undesired physiological reaction, such as emesis.This type of adverse agent can be used with any kind of therapeuticagent including an opioid, a benzodiazepine, a barbiturate, or astimulant. Examples of emetic agents suitable for use as the adverseagent in the present invention includes any drug that safely andeffectively induces vomiting after administration including, but notlimited to, ipecac and apomorphine.

5.4 Active Agent

The active agent of the present invention may or may not be formulatedin a plurality of particles.

Any kind of active agent can be used in the dosage forms of the presentinvention. Examples of useful active agents include, but are not limitedto, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmicagents, anti-bacterial agents, anti-viral agents, anti-coagulants,anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents,anti-gout agents, anti-hypertensive agents, anti-malarials,anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents,erectile-dysfunction-improvement agents, immunosuppressants,anti-protozoal agents, anti-thyroid agents, anxiolytic agents,sedatives, hypnotics, neuroleptics, β-blockers, cardiac ionotropicagents, corticosteroids, diuretics, anti-parkinsonian agents,gastrointestinal agents, histamine receptor antagonists, keratolytics,lipid regulating agents, anti-anginal agents, cox-2-inhibitors,leukotriene inhibitors, macrolides, muscle relaxants, nutritionalagents, opioid analgesics, protease inhibitors, sex hormones,stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesityagents, cognition enhancers, anti-urinary incontinence agents,nutritional oils, anti-benign prostate hypertrophy agents, essentialfatty acids, and non-essential fatty acids. The active agent particlescan comprise more than one active agent.

More specific examples of active agents include, but are not limited to,opioids, benzodiazepines, barbiturates, and stimulants, such asmethylphenidate and amphetamines, dronabinol, glutethimide,methylphenidate, nabilone, anabolic steroids, methylprylon,ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline,levomethadyl, benzphetamine, chlorphentermine, diethylpropion,phentermine, mebutamate, chlortermine, phenylacetone, dronabinol,nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde,midazolam, and detropropoxyphene.

In certain embodiments, the active agent is an opioid agonist. Usefulopioid agonists include, but are not limited to, alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, pantopon, papaveretum,paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, propylhexedrine,sufentanil, tilidine, tramadol, pharmaceutically acceptable saltsthereof, and mixtures thereof.

In certain embodiments, the opioid agonist is selected from the groupconsisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine,levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyland derivatives thereof, dipipanone, heroin, tramadol, etorphine,dihydroetorphine, butorphanol, levorphanol and mixtures thereof. In oneembodiment, the opioid agonist is oxycodone, hydromorphone orhydrocodone.

The term “benzodiazepines” refers to benzodiazepine and drugs that arederivatives of benzodiazepine and are able to depress the centralnervous system. Benzodiazepines include, but are not limited to,alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam,estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam,oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate andmixtures thereof.

Barbiturates refer to sedative-hypnotic drugs derived from barbituricacid (2, 4, 6,-trioxohexahydropyrimidine) Barbiturates include, but arenot limited to, amobarbital, aprobarbotal, butabarbital, butalbital,methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital,secobarbital and mixtures thereof.

Stimulants refer to drugs that stimulate the central nervous system.Stimulants include, but are not limited to, amphetamines, such asamphetamine, dextroamphetamine resin complex, dextroamphetamine,methamphetamine, methylphenidate and mixtures thereof.

The active agent can be an agent intended for delivery to the colon,including, but not limited to, agents that act locally in the colonicregion to treat a colon diseases such as irritable bowel syndrome,irritable bowel disease, Crohns disease, constipation, post operativeatony, gastrointestinal infections, and therapeutic agents that deliverantigenic material to the lymphoid tissue. Active agents for thetreatment of colon disease include, but are not limited to 5-ASA;steroids, such as hydrocortisone and budesonide; laxatives; stoolsofteners; octreotide; cisapride; anticholinergics; opioids; calciumchannel blockers; DNA for delivery to the cells of the colon;glucosamine; thromboxane A₂ synthetase inhibitors, such as Ridogrel;5HT3-antagonists, such as ondansetron; antibodies against infectiousbacteria, such as Clostridium difficile; and antiviral agents, forexample, for the prophylaxis of HIV.

Alternatively, the active agent can be an agent that is systemicallyactive and for which absorption is improved in the colon region. Suchdrugs include polar compounds such as: heparins; insulin; calcitonins;human growth hormone (HGH); growth hormone releasing hormone (GHRH);interferons; somatostatin and analogues such as octreotide andvapreotide; erythropoietin (EPO); granulocyte colony stimulating factor(GCSF); parathyroid hormone (PTH); luteinising hormone releasing hormone(LHRH) and analogues thereof; atrial natriuretic factor (ANF);vasopressin; desmopressin; calcitonin gene related peptide (CGRP); andanalgesics.

The active agent particles can further comprise hydrophobic materials,binders, plasticizers, excipients, and combinations thereof. Suitablematrix materials include those which allow release of the active agentat a rate sufficient to achieve the desired result, e.g., immediaterelease or sustained release. In one embodiment, permeable matrixmaterial is used, allowing for diffusive release of the opioid agonistinto the gastrointestinal fluid.

5.5 Adverse Agent Particles

In accordance with the present invention, the adverse agent isformulated in a co-extruded multilayer particle. In certain preferredembodiments, the adverse agent is sequestered in a co-extruded, twolayer particle comprising a sheath which at least partially surroundsthe core, and, preferably surrounds a majority of the core. For example,FIG. 1 is a perspective view of one non-limiting embodiment of thepresent invention comprising a co-extruded, cylindrical particle (10).The sequestered adverse agent is contained within a core (12). Themajority of the core is surrounded by a sheath (14). For example, thecore can be cylindrical with the sheath covering the outer curvedsurface (13) of the core in the radial direction, leaving at least oneend (17) of the core uncovered in the axial direction. In FIG. 1, anuncovered area of the core at one end of the cylindrical particle (16)is depicted by the shaded area (17).

5.5.1 Core

The sequestered adverse agent-containing core of the present inventionpreferably comprises a hydrophobic matrix material. Hydrophobic matrixmaterials useful in the present invention include those that are knownin the art to be insoluble or to have a low solubility in thegastrointestinal tract. Such materials include, but are not limited to,a hydrophobic material selected from the group consisting of acrylic andmethacrylic acid polymers and copolymers, and alkylcelluloses. Thematrix can also include additional hydrophobic materials such as zein,shellac, hydrogenated castor oil, hydrogenated vegetable oil or mixturesthereof. Although insoluble, such hydrophobic materials can degrade overtime, thereby eventually releasing some portion of the adverse agent.One of ordinary skill in the pharmaceutical arts can control the rate ofsuch release by, for example, altering the content of the hydrophobicmatrix material in the adverse agent core in order to limit or greatlylimit the in vivo release of the sequestered adverse agent. This andother methods of sequestering the adverse agent will be known in the artor can be determined by routine experimentation.

In one embodiment, the hydrophobic matrix material comprises acrylicpolymers. Examples of suitable acrylic polymers include, but are notlimited to acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylates, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymers,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, poly(methacrylic acid) (anhydride), methyl methacrylate,polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acidanhydride), and glycidyl methacrylate copolymers. Additional examples ofsuitable acrylic polymers include, but are not limited to, acrylicresins comprising copolymers synthesized from acrylic and methacrylicacid esters (e.g., the copolymer of acrylic acid lower alkyl ester andmethacrylic acid lower alkyl ester) containing about 0.02 to 0.03 molesof a tri (lower alkyl) ammonium group per mole of acrylic andmethacrylic monomer.

The acrylic polymer can comprise one or more ammonio methacrylatecopolymers. Ammonio methacrylate copolymers are well known in the art,and are fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups. In order toobtain a desirable dissolution profile for a given therapeutic agent, itmight be necessary to incorporate two or more ammonio methacrylatecopolymers having differing physical properties. For example, it isknown that by changing the molar ratio of the quaternary ammonium groupsto neutral (meth)acrylic esters, the permeability properties of theresultant coating can be modified. One of ordinary skill in the art willreadily be able to combine monomers to provide a copolymer that releasesthe therapeutic agent at the desired release rate. Copolymers ofacrylate and methacrylate having a quaternary ammonium groupfunctionality are commercially available as EUDRAGIT RS™ and EUDRAGITRL™ (Röhm Pharma, GmbH, Darmstadt, Germany). Preferred ammoniomethacrylate resins include EUDRAGIT RS™ in all forms, such as EUDRAGITRS PO™. EUDRAGIT RS™ is known to be a water-insoluble copolymer of ethylacrylate (EA), methyl methacrylate (MM) and trimethylammonium ethylmethacrylate chloride (TAM) in which the molar ratio of EA:MM:TAM is1:2:0.01; see, e.g., U.S. Pat. No. 6,306,391. EUDRAGIT RS PO™ is knownto be a powdered form of EUDRAGIT RS™; see, e.g., U.S. Pat. No.5,492,692.

In one embodiment the hydrophobic matrix material comprises a waterinsoluble cellulose polymer. In certain embodiments, the cellulosepolymer is a cellulose ether, a cellulose ester, or a cellulose esterether. Preferably, the cellulose polymers have a degree of substitution(“D.S.”) on the anhydroglucose unit of from about zero up to andincluding about 3. As used herein the term D.S. means the average numberof hydroxyl groups present on the anhydroglucose unit of the cellulosepolymer that are replaced by a substituent group. Representativecellulose polymers include, but are not limited to, polymers selectedfrom cellulose acylate, cellulose diacylate, cellulose triacylate,cellulose acetate, cellulose diacetate, cellulose triacetate, mono-,di-, and tricellulose alkanylates, mono-, di-, and tricellulosearoylates, and mono-, di-, and tricellulose alkenylates. Exemplarycellulose polymers include cellulose acetate having a D.S. of from about1 to about 2 and cellulose acetate having a D.S. of from about 2 toabout 3. Preferably, the cellulose polymer is ethylcellulose, celluloseacetate, cellulose propionate (low, medium, or high molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, or cellulose triacetate. A more preferred celluloseis ethylcellulose.

More specific cellulose polymers include cellulose propionate having aD.S. of about 1.8; cellulose acetate butyrate having a D.S. of about1.8; cellulose triacylate having a D.S. of about 2.9 to 3, such ascellulose triacetate, cellulose trivalerate, cellulose trilaurate,cellulose tripalmitate, cellulose trisuccinate, and cellulosetrioctanoate; cellulose diacylates having a D.S. of about 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentanoate; and coesters of cellulose such ascellulose acetate butyrate, cellulose acetate octanoate butyrate, andcellulose acetate propionate.

The core can generally comprise from about 30% to about 99% by weight ofone or more hydrophobic matrix materials, preferably from about 50% toabout 95% by weight of the one or more hydrophobic matrix materials,more preferably from about 60% to about 95% by weight of the one or morehydrophobic matrix materials.

The adverse agent-containing core can optionally comprise one or morebinders, additional retardants, plasticizers, and/or excipients. Bindersare useful for maintaining the integrity of the matrix and may also helpto delay the release of an agent into the bodily fluid. Examples ofbinders include natural and synthetic waxes, water insoluble waxes,fatty alcohols, fatty acids, hydrogenated fats, fatty acid esters, fattyacid glyercides, hydrocarbons, and hydrophobic and hydrophilic polymershaving hydrocarbon backbones, and mixtures such as, stearyl alcohol,stearic acid, and water soluble polymers such as hydroxycelluloses.

Plasticizers are useful when the hydrophobic matrix material containscellulose polymer or an acrylic polymer. Non-limiting examples ofsuitable plasticizers include, e.g., acetyl triethyl citrate and/oracetyl tributyl citrate.

The adverse agent core can also include other excipients, which may beadded to improve the processability of the formulation during extrusionand/or to improve the properties of the final product. Non-limitingexamples of liquid excipients include water and oils, including those ofpetroleum, animal, vegetable, or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil, castor oil, triglycerides and thelike. Examples of solid excipients include magnesium stearate, saline,gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, ureaand the like. Coloring agents may also be added to the core.

5.5.2 Sheath

The co-extruded, sequestered adverse agent-containing particle of thepresent invention comprises a sheath which at least partially surroundsthe adverse agent-containing core, and preferably surrounds a majorityof the adverse agent-containing core. In one preferred embodiment, thesheath surrounds a majority, but not all, of the core. The sheathpreferably comprises a hydrophobic matrix material and, optionally,binders, additional retardants, plasticizers and excipients. While thesheath can contain a small percentage of adverse agent, it is preferredthat the sheath does not contain any adverse agent.

In one embodiment, the hydrophobic material of the sheath comprises oneor more materials selected from the group consisting of acrylic andmethacrylic acid polymers and copolymers, and water insolublealkylcelluloses as described above for the core. The sheath canoptionally comprise one or more additional hydrophobic materials, suchas shellac, zein, hydrogenated castor oil, hydrogenated vegetable oiland mixtures thereof as described above for the core.

The hydrophobic matrix material used in the sheath may or may not be thesame as that used in the adverse agent-containing core. Although thehydrophobic material used in the sheath will preferably be substantiallyinsoluble in the gastrointestinal tract, this material could dissolve orbiodegrade in vivo to some limited extent over time, thereby permittingthe in vivo release from the core of a small amount of the adverseagent. One of ordinary skill in the pharmaceutical arts can control andlimit the rate of such release, for example, by altering the compositionof the sheath, increasing the thickness of the sheath, surrounding alarger portion of the core with the sheath, varying the size and/ordimensions of the core and/or varying the composition of the sheathand/or core. These and other methods will be known to one of ordinaryskill in the art or can be determined by routine experimentation in viewof this disclosure.

The sheath can comprise from about 10% to about 99% by weight,preferably from about 40% to about 95% by weight, and more preferablyfrom about 60% to about 90% by weight of the one or more hydrophobicmatrix materials.

The sheath can further comprise one or more additional retardants or oneor more binders or plasticizers or excipients, or some combinationthereof, such as those described above for the adverse agent-containingcore.

5.6 Active Agent Particles

The present invention includes compositions and dosage forms comprisingan active agent which can be formulated into any suitable dosage form,including but not limited to, active agent containing particles. Thecompositions and dosage forms of the invention can provide any rate ofrelease of the active agent in vivo following oral administration, suchas immediate release or controlled release. In preferred embodiments,active agent-containing particles provide a controlled release of theactive agent, such as an opioid agonist. Formulations and methods ofmanufacture of controlled release dosage forms of opioid antagonists areknown in the art. For example, U.S. Pat. Nos. 5,958,452; 5,965,161;5,968,551; 6,294,195 and 6,335,033, each of which is expresslyincorporated herein by reference, disclose controlled release oralopioid agonist dosage forms. The disclosure of one or more of suchpatents includes details such as formulations, matrix materials, coatingmaterials, hydrophobic materials, retardants, binders, plasticizers, andexcipients, as well as methods of coating beads, methods of formingspheroids, granulation methods (wet and dry), and extrusion methods forforming tablets, caplets and multiparticulate capsules for controlledrelease oral opioid agonist dosage forms.

The active agent can be dispersed in a matrix which provides controlledrelease of the active agent in vivo following oral administration. Anycontrolled-release matrix can be used to make active agent particles.Certain controlled-release matrices are known for oral formulations(see, e.g., Remingtons Pharmaceutical Sciences, 18^(th) ed. MackPublishing Co., Easton, Pa., 1990, p. 1684-1685). In addition to thecontrolled release matrices disclosed in the above-identified patents,other examples of useful controlled-release matrices are described inU.S. Pat. Nos. 6,143,328; 6,063,405; 5,462,747; 5,451,409; 5,334,392;5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351, 5,356,467, and5,472,712, the contents of which are expressly incorporated herein byreference.

The controlled-release matrix can include fusible hydrophobicmaterial(s), optionally combined with hydrophilic material(s). Thehydrophobic fusible material(s) can be, for example, a hydrophobicpolymer or a natural or synthetic wax or oil, such as hydrogenatedvegetable oil or hydrogenated castor oil, which can, for example, have amelting point of from about 45° C. to about 100° C., and in oneembodiment from about 50° C. to about 90° C. The hydrophilic materialcan be a hydrophilic polymer such as a hydroxycellulose; a water solublefusible material, such as polyethylene glycol; or a water solubleparticulate material, such as dicalcium phosphate or lactose.

While any known method can be used to make controlled release opioidagonist particles for use in the present invention, a preferred methodis melt-extrusion of the opioid agonist with matrix materials.

The active agent dispersed in a controlled-release matrix can beprepared by formulating, e.g., using dry or wet granulation or byblending, the active agent with a component other than the fusiblecomponent. Suitable non-fusible materials for inclusion in a controlledrelease matrix include, but are not limited to, any of the following:

(a) Hydrophilic or hydrophobic polymers, such as gums, cellulose ethers,protein-derived materials, nylon, acrylic resins, polylactic acid,polyvinylchloride, starches, polyvinylpyrrolidones, and celluloseacetate phthalate. Of these polymers, cellulose ethers, for example,substituted cellulose ethers such as alkylcelluloses (e.g.,ethylcellulose), C₁-C₆ hydroxyalkylcelluloses (e.g.,hydroxypropylcellulose and hydroxyethyl cellulose), and acrylic resins(e.g., methacrylates such as methacrylic acid copolymers) may be used.The controlled-release matrix can conveniently contain from about 1% toabout 80% (by weight) of the hydrophobic and/or hydrophilic polymer.(b) Digestible, long chain (C₈-C₅₀, in one embodiment C₈-C₄₀)substituted or unsubstituted hydrocarbons, such as fatty acids;hydrogenated vegetable oils; fatty alcohols, such as lauryl, myristyl,stearyl, cetyl or, in one embodiment cetostearyl alcohol; glycerylesters of fatty acids, for example, glyceryl monostearate; mineral oils;and waxes, such as beeswax, glycowax, castor wax, and carnauba wax.Hydrocarbons having a melting point of from about 25° C. to about 90° C.are used in one embodiment. Of these long chain hydrocarbon materials,fatty (aliphatic) alcohols are useful in one embodiment. Thecontrolled-release matrix can contain up to about 60% (by weight) of atleast one digestible, long chain hydrocarbon.(c) Polyalkylene glycols. The controlled-release matrix can contain upto about 60% (by weight) of at least one polyalkylene glycol.

A suitable controlled-release matrix for use in the oral dosage form ofthe invention comprises one or more cellulose ethers or acrylic resins,one or more C₁₂-C₃₆ aliphatic alcohols, in one embodiment C₁₂-C₂₂,aliphatic alcohols, and/or one or more hydrogenated vegetable oils. Aparticular suitable matrix comprises one or more alkylcelluloses, one ormore C₁₂-C₃₆ aliphatic alcohols, in one embodiment C₁₂-C₂₂, aliphaticalcohols, and optionally one or more polyalkylene glycols. In anotherembodiment the matrix contains from about 0.5% to about 60% (by weight),and in another embodiment, from about 1% to about 50% of the celluloseether.

The acrylic resin is, for example, a methacrylate such as methacrylicacid copolymer USNF Type A (EUDRAGIT L™), Type B (EUDRAGIT S™), Type C(EUDRAGIT L 100-55™), EUDRAGIT NE 30 D™, EUDRAGIT E™, EUDRAGIT RL™, orEUDRAGIT RS™ (commercially available from Röhm Pharma GmbH, Darmstadt,Germany). In one embodiment, the matrix contains from about 0.5% toabout 95% by weight, and in another embodiment from about 10% to about50% by weight of the acrylic resin.

In the absence of polyalkylene glycol, the matrix in one embodimentcontains from about 1% to about 40%, in another embodiment from about 2%to about 36% (by weight) of the aliphatic alcohol. When polyalkyleneglycol is present in the oral dosage form, then the combined weight ofthe aliphatic alcohol and the polyalkylene glycol in one embodimentconstitutes from about 2% to about 40%, in another embodiment from about2 to about 36% (by weight) of the matrix.

The polyalkylene glycol can be, for example, polypropylene glycol or, inone embodiment, polyethylene glycol. The number average molecular weightof the polyalkylene glycol is in one embodiment from about 200 to about15,000 Daltons, and in another embodiment from about 400 to about 12,000Daltons.

The controlled-release matrix containing the active agent can readily beprepared by dispersing the therapeutic agent in the components of thematrix using conventional pharmaceutical techniques including, but notlimited to, melt-granulation, wet-granulation, dry-blending,dry-granulation, and co-precipitation.

The controlled-release formulations release, in one embodiment, slowlyrelease, the therapeutic agent when ingested and exposed to gastricand/or intestinal fluids.

5.7 Co-Extrusion Process

The present invention also relates to methods for preparing apharmaceutical composition or dosage form comprising a sequesteredadverse agent by co-extruding, such as by melt co-extruding, a corecomprising an adverse agent and a sheath which at least partiallysurrounds the core. In one embodiment, the invention relates to methodsof making a plurality of sequestered adverse agent particles by a)co-extruding a core comprising an adverse agent, and a sheath which atleast partially surrounds the core and preferably surrounds a majorityof the core, to form extrudate strands; and b) cutting the extrudatestrands to form a plurality of sequestered adverse agent particles. Inone embodiment, the core comprises an adverse agent and a hydrophobicmaterial and the sheath comprises a hydrophobic material.

In another embodiment, the invention relates to methods of making adosage form comprising a) forming a plurality of first particlescomprising an active agent; b) co-extruding a plurality of secondparticles comprising a sequestered adverse agent, wherein the secondparticles comprise a core comprising an adverse agent and a hydrophobicmaterial, and a sheath comprising a hydrophobic material which at leastpartially surrounds the core, and preferably surrounds a majority of thecore; and c) combining the first and second particles together.

Generally, methods of preparing active agent-containing compositions orparticles by extrusion and/or co-extrusion are well known. See, forexample, U.S. Pat. Nos. 5,958,452, 5,965,161 and 6,335,033, each ofwhich is expressly incorporated herein in its entirety, which discloseknown methods for extruding and forming pharmaceutical dosage forms,including dosage forms consisting of particles. Co-extrusion methods toform two layer compositions or particles for administering an activeagent are also known. See, for example, U.S. Patent Application No.2002/0119197 A1, which is expressly incorporated herein in its entirety.There is, however, no suggestion in the prior art of a co-extrusionmethod to form compositions or dosage forms comprising a sequesteredingredient, such as a sequestered adverse agent.

In accordance with the present invention, a co-extrusion process is usedto make pharmaceutical compositions or dosage forms comprising asequestered adverse agent which is released in a limited, if any, amountin vivo following intact administration as intended to a patient. In oneembodiment, the composition or dosage form comprises a co-extruded,sequestered adverse agent cylindrical particle having a core containingthe adverse agent and which is at least partially radially surroundedalong its length by a sheath that preferably does not contain anyadverse agent. In a further embodiment, the co-extruded particlescontaining a sequestered adverse agent, such as an opioid antagonist,are placed in a gelatin capsule with particles containing an activeagent.

The present invention further relates to methods of preparing aparticulate sequestered adverse agent useful in a dosage form,comprising charging an adverse agent core formulation comprising anadverse agent and a hydrophobic matrix material into a first extruder;charging a sheath formulation comprising a hydrophobic matrix materialinto a second extruder; heating the formulations in the first and secondextruders; co-extruding the formulations to form a strand comprising anadverse agent core radially surrounded by a sheath; and rendering thestrand into particles.

An example of an apparatus useful for the co-extrusion process of thepresent invention includes two powder-feeder hoppers, one for loadingthe adverse agent core components and one for loading the sheathcomponents. The adverse agent core components include the adverse agentand the hydrophobic matrix material, and optionally additional materialsincluding, but not limited to, additional retardants, binders,plasticizers and excipients, as described above. The sheath componentsinclude a hydrophobic matrix material and additional materialsincluding, but not limited to, additional retardants, binders,plasticizers and excipients as described above. The contents of eachhopper are charged to an extruder. The outlet of each extruder isattached to the same coaxial die having multiple co-axial outletorifices, thereby forming strands of extrudate with the adverse agent inthe core of the strand and the sheath radially surrounding the core soas to sequester the adverse agent.

Each extruder can, for example, be equipped with single or twin screwsand heated barrels. Each screw extruder can, independently, be of the(i) counter-rotating (i.e., driven in opposite directions of rotation)non-intermeshing; (ii) co-rotating (i.e., driven in the same directionof rotation) non-intermeshing; (iii) counter-rotating intermeshing; or(iv) co-rotating intermeshing type. Each extruder can, independently,have a sole discharge port located at the end of its housing or a radialdischarge port. Each screw extruder can, independently, have drive meansat each end of the screw or a drive means present at only one end. Eachscrew extruder can, independently, have a length to diameter, or L/D,ratio of from 5-70, preferably from 20-60. Those in the art are familiarwith such apparatuses, e.g., a Leistritz twin screw extruder having avacuum attachment, a Leistritz Micro 18/GL 40D twin screw extruder, or aWarner & Pfleiderer model ZSK-30 twin screw extruder.

The temperature of each individually adjustable barrel zone of eachextruder is set to the required temperature for a given formulation, andthe extruder is allowed to thermally equilibrate, typically for about 30minutes. The inside pressure of the twin screw extruder can bemaintained from about 600 to about 980 mbar negative.

After a steady state temperature is attained, the contents of eachpowder-feeder hopper are fed into the separate pre-heated extruder,thereby forming in each extruder an intimately mixed molten masstypically from about 30° C. to about 200° C. in temperature, preferablyfrom about 50° C. to about 150° C., through heating and mixing, as it isdriven through a series of zones by intermeshing screws and kneadingelements. Optionally, a vent port can be present in the extruder. If itis desired to add a liquid component, independently of any powderedformulation, to a molten mass, the liquid can be injected into theextruder by any known means, for example, by an injection port suppliedby a positive displacement pump, such as a gear pump.

The molten masses exiting each extruder are combined in a coaxial die,which is optionally downstream of a combining block and/or a main gateadaptor, then passed through the exit orifice of the die, therebyforming a single or multiple extruded strand(s) comprising an adverseagent core and a sheath sequestering the core. Generally, the rotationspeed, in rpm, of each extruder is adjusted such that their combinedoutput, at the die orifice, is from about 1 to about 20 kg/hr orgreater, preferably from about 6 to about 8 kg/hr. The rotation speed ofeach extruder is one of the parameters that can be adjusted so that theoutput of each extruder yields the desired ratio of the core to thesheath.

The dimensions and/or cross-sectional profile of the die exit orificecan be adjusted to vary the thickness and shape of the resulting strand.For example, the orifice is not limited to a circular cross-sectionalprofile, but can be elliptical, square, rectangular, hexagonal,triangular, 5-pointed star-shaped, etc. Typically, an orifice having acircular cross-section can be adjusted to provide a strand having adiameter from about 0.1 mm to about 5.0 mm. The shape of the strand isdetermined by, among other factors, the shape of the die exit orificeopening and the method of rendering the strand into particles.

The strand produced from the co-extrusion process is thereafter conveyedaway from the orifice and solidified by methods known to those in theart, for example, using a fan-cooled tunnel or a continuous movable beltupon which the strand(s) congeal and harden upon cooling. The strand isdirected to a suitable device to render the extruded strand intoparticles by methods known to those in the art, for example, using lasercutting, a hot wire-cutter or a guillotine. Rendering the strand intoparticles can occur before, during or following congealing.

In one embodiment, the hardened strand which results from theco-extrusion process is cut by a pelletizer, which can utilize rollers,a fixed knife, a rotating cutter and the like. The roller speed andcutter speed are set so as to produce particles of the desired size andrelease characteristics. Suitable instruments and systems are availablefrom distributors such as Rand Castle Inc. of New Jersey. Other suitableapparatus will be apparent to those of ordinary skill in the art.

In one embodiment, the co-extruded strand is cut to form a number ofcylinders as shown in FIG. 1, where the adverse agent-containing core isexposed at both ends of the cylinder. In any case, the compositions ofthe adverse agent-containing core and the sheath should be formulatedaccordingly to limit the rate of in vivo release of the sequesteredadverse agent.

In addition, it is to be understood that the particles can be anygeometrical shape within this size range, such as a bead, a seed, apellet, etc., depending upon the die exit orifice. In one embodiment,the particulates formed will be spheroids with a diameter of from about0.1 mm to about 3.0 mm. In another embodiment, the particulates formedwill be cylindrical with a length of from about 0.1 to about 3.0 mm anda diameter of from about 0.1 to about 3.0 mm.

It will be apparent to one of ordinary skill in the art ofpharmaceutical extrusion that the dimensions of the core and the sheathcan be varied. For example, by changing the die orifice, the diameter ofthe core and the thickness of the sheath can be varied. Typically, thediameter of the core is from about 0.05 mm to about 2.95 mm, preferablyabout 0.3 mm to about 2.0 mm. The thickness of the sheath is determinedby the stability of the hydrophobic matrix material and the thickness ofthe core. Typically, the thickness of the sheath is from about 0.05 mmto about 2.95 mm, preferably about 0.3 mm to about 2.0 mm. The diameterof the core and the thickness of the sheath are typically adjusted toprovide a particulate with a cross-sectional diameter of about 3.0 mm orless. By routine experimentation, one skilled in the art of extrusioncan modify the parameters in order to prepare the adverseagent-containing particles with suitable dimensions.

Following cutting, the co-extruded particles are collected and can beused in any manner for which such solid pharmaceutical composition isused. Optionally, following cutting, the particles are passed through aseparator using #16 TBC (approximately 0.054″) and #26 TBC(approximately 0.031″) opening screens and collected. In a preferredembodiment, co-extruded particles containing an adverse agent andparticles containing an active agent are placed together in hard gelatincapsules for oral dosage to patients.

5.8 Methods for Administration

The present invention is also directed to methods for treating acondition in a patient comprising administering a dosage form of thepresent invention to a patient in need of said treatment. The dosageform, can be, for example, an oral dosage form, such as a tablet orcapsule, or a rectal or vaginal dosage form, such as a suppository. Inone embodiment, the condition is pain and the dosage form comprises anopioid and a sequestered opioid antagonist. In certain embodiments, thedosage form is administered to a patient twice a day, and in otherembodiments, once a day.

5.8.1 Amount Per Dosage Unit

In the dosage form of the present invention, the amount of the activeagent per dosage unit is that which is an effective amount for itsparticular indication and is independent of the amount of theadverse-effect agent. For example, if the therapeutic agent is an opioidagonist, the amount of the opioid agonist in the dosage form of thepresent invention is generally from about 1 mg to about 800 mg, in oneembodiment from about 5 mg to about 160 mg. One of ordinary skill in theart can readily determine, without undue experimentation, the amount oftherapeutic agent needed for a particular indication.

The amount of the adverse agent in the dosage form of the presentinvention is such that the adverse agent can give the intended adverseeffect if, when tampered with, a substantial amount of the adverse agentis released immediately from the dosage form and absorbed into ananimal's blood. When, upon tampering with the dosage form, the adverseagent is intended to reduce or eliminate one or more of thepharmacological effects of the active agent, such as euphoria, theamount of the adverse agent in the dosage form is at least sufficient toreduce or eliminate those effects of the active agent when substantialamounts of both agents are released from the dosage form and absorbedinto an animal's blood after tampering has occurred.

When the adverse effect agent is an opioid antagonist, such asnaltrexone or nalmefene, the amount of the opioid antagonist present ina dosage form of the present invention can be from about 0.2 mg to about50 mg, or from about 0.5 mg to about 5 mg. The opioid antagonistscyclazocine and naltrexone, when administered orally, retain much oftheir efficacy with a long duration of action, approaching 24 hours.Amounts of less than about 10 mg of these opioid antagonists aretypically used in oral formulations of the invention.

When, upon tampering, the adverse effect agent is intended to cause anundesired physiological reaction, such as emesis, the amount of theadverse-effect agent in the dosage form is at least sufficient to causesuch effect upon release after tampering has occurred.

In certain embodiments of the present invention, the ratio of thetherapeutic agent to the adverse-effect agent in the dosage form can befrom about 1:1 to about 50:1 by weight, in one embodiment from about 1:1to about 20:1 by weight. In certain other embodiments, the ratio may canbe about 1:1 to about 10:1 by weight.

In non-limiting embodiments in which the opioid agonist is hydrocodone,the sustained-release dosage forms can include analgesic doses fromabout 5 mg to about 80 mg of hydrocodone per dosage unit. Innon-limiting embodiments where the opioid agonist is hydromorphone, itcan be included in an amount from about 2 mg to about 64 mghydromorphone hydrochloride per dosage unit. In non-limiting embodimentsin which the opioid agonist is morphine, it can be present in the dosageform from about 2.5 mg to about 800 mg morphine per dosage unit. Innon-limiting embodiments in which the opioid agonist is oxycodone, thedosage forms can include from about 2.5 mg to about 800 mg oxycodone,and in another embodiment from about 20 mg to about 30 mg oxycodone perdosage unit. Controlled-release oxycodone formulations are known in theart. In a non-limiting embodiment, the opioid agonist can be tramadol inan amount from about 25 mg to 800 mg tramadol per dosage unit. Thedosage form can contain more than one opioid agonist, and the doses ofeach can be adjusted accordingly.

The term “unit dose” is defined for purposes of the present invention asthe total amount of dosage form needed to administer a single desireddose of active agent (e.g., opioid agonist) to a patient.

5.8.2 Methods for Rectal Administration

As noted above, the present invention is also directed to administrationof a dosage form comprising co-extruded, sequestered adverse agentparticles and active agent particles to a patient in need thereof in theform of a suppository for absorption through the rectum. Whenadministered as a suppository, the composition preferably comprises abase material. Any base material can be used provided it does notdissolve the particulates. For example, cocoa butter is a traditionalsuppository base material, which can be modified by addition of waxes toraise its melting point slightly. Water-miscible suppository basematerials comprising, particularly, polyethylene glycols of variousmolecular weights can be included. When administered as a suppository,the combined concentration of the first and second plurality ofparticles in the suppository formulation is, typically, from about 5.0%to about 80% by weight of the composition.

5.8.3 Kits

The present invention is also directed to a kit comprising at least onedosage form of the invention. In one embodiment, the dosage form ispresent in a container, e.g., a bottle or box. In another embodiment,the kit further comprises a set of instructions directing the use of thedosage form to treat a patient, e.g., for pain. In one embodiment, theinstructions may be a printed label affixed to or printed on thecontainer. In another embodiment, the instructions may comprise aprinted sheet inserted into the container or into the packaging whichcontains the container. The instructions may also state that the dosageform and/or its usage are designed to reduce abuse, misuse or diversionof the dosage form.

6. EXAMPLES

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the presentinvention.

6.1 Example 1: Preparation of Unsheathed Sequestered Opioid AntagonistParticles by Melt Extrusion

Example 1 describes the preparation of unsheathed, sequestered opioidantagonist particles. The formulation of the feed to the extruder usedto prepare the opioid antagonist-containing particles is provided inTable 1 below.

TABLE 1 Formulation Used to Prepare Unsheathed Sequestered NaltrexoneHydrochloride Particles by Melt Extrusion. Ingredient Amount/Unit (mg)Content in Feed (wt. %) Naltrexone 2 1.7 hydrochloride EUDRAGIT RS PO 8872.7 Stearyl alcohol 15 12.4 Stearic acid 15 12.4 BHT 1 0.8 Total 121100

Unsheathed, sequestered opioid antagonist (naltrexone HCl) particleswere prepared by charging the ingredients of Table 1 to thepowder-feeder hopper of a Leistritz twin screw extruder having a vacuumattachment. The extruder was equipped with twin-screws and a multi-zoneheated barrel. The initial zones were maintained at a target temperatureof 50±2° C., intermediate zones were maintained at a target temperatureof 105±3° C., and final zones were maintained at a target temperature of70±2° C. The inside pressure of the twin screw extruder was maintainedfrom about 600 to about 980 mbar negative. The inlet end of the extruderbarrel was adjacent to the powder-feeder hopper, and the outlet end wasattached to a die with circular cross-section orifices about 1 mm indiameter. The extruder was allowed to thermally equilibrate for 30minutes.

The rotation speed of the extruder was set to a level to produce thedesired output, and the formulation was heated with mixing until amolten mass formed. The resultant viscous mass was transported throughthe pre-heated barrel to the die, and the viscous formulation wasextruded through circular cross-section die orifices about 1 mm indiameter as spaghetti-like strands. The extrudate was transported on acontinuous movable belt to a pelletizer as it congealed and hardened.The resultant hardened strands are pelletized with a Rand Castle Inc.roller knife into cylindrical particles of about 1.0 mm in diameter andabout 1.0 mm in length.

After the pellets were manufactured, 121 mg of pellets were encapsulatedin hard gelatin capsules, rendering capsules containing 2 mg ofNaltrexone HCl. These capsules were then tested using the followingdissolution methodology:

The dissolution rate of the capsules was measured by the USP BasketMethod. The apparatus consisted of a USP Type I basket (100 rpm). Thecapsules were contacted with 700 mL simulated gastric fluid (SGF), (pH1.2 without enzyme) at 37° C. for one hour. Thereafter, the capsuleswere contacted with 900 mL simulated intestinal fluid (SIF) (pH 7.5without enzyme) for the duration of the test. The rate of dissolutionwas determined by assaying each of the fluids using HPLC.

Capsules prepared by the above process exhibited dissolution rates setforth in Table 2.

TABLE 2 Rate of Dissolution of Unsheathed Sequestered Core ParticlesContaining Naltrexone Hydrochloride in Hard Gelatin Capsules. Time (hr)1 2 4 8 12 24 36 Mean % dissolved 1.3 2.6 2.9 3.6 4.0 5.2 6.2

6.2 Example 2: Preparation of Sheathed Sequestered Opioid AntagonistParticles by Melt Co-Extrusion

Example 2 describes a prophetic example of a process which should besuitable for the preparation of a sheathed, sequestered opioidantagonist particle by melt co-extrusion, where the core contains thesequestered opioid antagonist naltrexone hydrochloride and a majority ofthe core is surrounded by a sheath which does not contain anynaltrexone. More particularly, the core is cylindrical, and the sheathsurrounds the length of the core in the radial direction while the endsof the core are exposed in the axial direction. The formulations of thefeed to the core extruder and the feed to the sheath extruder that maybe used in this prophetic example are provided in Table 3.

TABLE 3 Formulation to Prepare Sheathed Sequestered NaltrexoneHydrochloride Particles by Melt Co-extrusion. Ingredient Amount (mg)Content (wt. %) Core Formulation: 61 50.8 Naltrexone HCl 2 1.7 EUDRAGITRS PO 44 36.7 Stearyl alcohol 7 5.8 Stearic acid 7 5.8 BHT 1 0.8 SheathFormulation: 59 49.2 EUDRAGIT RS PO 44 36.7 Stearyl alcohol 15 12.5Total 120 100

The core of the sheathed, sequestered opioid antagonist (naltrexone HCl)particles can be prepared by 1) charging the core formulationingredients of Table 3 into the powder-feeder hopper of a Leistritz twinscrew core extruder having a vacuum attachment; and 2) charging thesheath formulation into the powder-feeder hopper of a Leistritz twinscrew sheath extruder having a vacuum attachment. Each extruder can beequipped with twin-screws and a multi-zone heated barrel. In eachextruder, the initial zones can be maintained at a target temperature of50±2° C.; intermediate zones can be maintained at a target temperatureof 105±3° C.; and final zones can be maintained at a target temperatureof 70±2° C. Each extruder can be allowed to thermally equilibrate for 30minutes. The inside pressure of each twin screw extruder can bemaintained from about 600 to about 980 mbar negative. The inlet of eachextruder barrel can be attached to the outlet end of the respectivepowder-feeder hopper. The outlet of the core extruder barrel can beconnected to the inlet of the core orifice of a co-extrusion die and theoutlet of the sheath extruder barrel can be attached to the inlet of thesheath orifice of the co-extrusion die. The extrudate strand which exitsthe co-extrusion die comprises a cylindrical core containing sequesterednaltrexone HCl which is surrounded in the radial direction by anannular-shaped sheath.

The rotation speed of each extruder can be set to a level to produce thedesired combined output, at the die orifice, such as 7 kg/hr. Theformulations can be heated with mixing until respective molten massesform. Each resultant viscous mass can then be transported through therespective extruder barrel to the respective co-extrusion die inlets.The extrudate can then be transported on a continuous movable belt to apelletizer as it congeals and hardens. The resultant hardened strandscan be pelletized with a Rand Castle roller knife into cylindricalparticles of about 0.5 to 1.5 mm in diameter and about 1.0 mm in length;for example about 0.8 to 1.4 mm in length and about 0.8 to 1.2 mmdiameter. In these particles, the average diameter of the core is about0.25 to 0.5 mm and the average thickness of the sheath is about 0.25 to0.5 mm.

After their manufacture, 120 mg of the co-extruded particles can beencapsulated in hard gelatin capsules described in Example 1 to providecapsules containing 2 mg of naltrexone hydrochloride.

The rate of dissolution of the naltrexone hydrochloride released shouldthen be measured as described in Example 1. The amount of naltrexonehydrochloride released from the co-extruded, sheathed, sequesteredopioid antagonist particles of Example 2 is expected to be less than theamount released from the particles of Example 1.

All patents, applications, publications, test methods, literature, andother materials cited above are hereby incorporated herein by reference.

1-31. (canceled)
 32. A method of making a plurality of adverse agent particles comprising: co-extruding a core composition and a sheath composition to form an extrudate stand; wherein the sheath composition radially surrounds at least a majority of the core composition, the core composition comprises an adverse agent and a hydrophobic material, and the sheath composition comprises a hydrophobic material; and cutting the extrudate strand at predetermined lengths to form a plurality of adverse agent particles.
 33. The method of claim 32, wherein the adverse agent is an opioid antagonist; and the particles have a size of about 0.1 mm to about 3.0 mm in all dimensions.
 34. The method of claim 32, wherein the adverse agent is sequestered.
 35. A method of making a dosage form comprising: (a) forming a plurality of first particles comprising an active agent; (b) forming a plurality of second particles comprising an adverse agent by co-extruding a core composition and a sheath composition to form an extrudate strand; wherein the sheath composition radially surrounds a portion of the core composition, the core composition comprises the adverse agent and a hydrophobic material, and the sheath composition comprises a hydrophobic material; and cutting the extrudate strand at predetermined lengths to form a plurality of second particles; and (c) adding the first particles and the second particles together in a form suitable for administration to a patient.
 36. The method of claim 35, wherein the first particles and the second particles 10 are substantially identical in appearance to each other.
 37. The method of claim 36, wherein the active agent is an opioid agonist and the adverse agent is an opioid antagonist.
 38. The method of claim 37, wherein the dosage form is an oral dosage form, and the first particles and the second particles each have a size of from about 0.1 mm to 15 about 3.0 mm in all dimensions.
 39. The method of claim 35, wherein the first particles and the second particles are placed into a capsule for administration to a patient.
 40. The method of claim 35, wherein the adverse agent is sequestered. 41-46. (canceled) 